The rockefeller university

Quaternary climatic fluctuations had a substantial influence on ecosystems, species distribution, phenology and genetic diversity, driving extinction, adaptation and demographic shifts during glacial periods and postglacial expansions. Integration of genomic data and environmental niche modelling can provide valuable insights on how organisms responded to past environmental variations and contribute to assessing vulnerability and resilience to ongoing climatic challenges. Among vertebrates, turtles are particularly vulnerable to habitat changes because of distinctive life history traits and the effect of environmental conditions on physiology and survival. We estimated contemporary heterozygosity (H) and effective population size (N e) using a high-quality chromosome-level reference genome we produced for the European pond turtle (Emys orbicularis) and reference genomes and whole genome sequence data available for 21 species of tortoises and freshwater turtles. We implemented environmental niche modelling (ENM) to estimate past habitat dynamics. We found recurrent cycles of population expansion and contraction over the last 10 Mya in all species, with a general pattern of decrease in N e correlated with temperature reduction after the last interglacial period. No correlation was found between habitat fluctuations during the Quaternary and past N e. Moreover, neither H nor mean N e was correlated to threat status as defined by IUCN Red List categories. Our results add to studies on other vertebrates showing the extent to which genetic parameters can aid the assessment of conservation status, and although genomic data may not always be consistent indicators of the level of threat, investigations of which genomic parameters could best represent essential biodiversity variables should be consistently supported.

The loss and mutation of Topoisomerase 3 beta (TOP3B), the only known eukaryotic topoisomerase with the ability to catalyze RNA strand passage reactions, is linked to schizophrenia, autism, and intellectual disability. Uniquely, TOP3B primarily localizes to the cytoplasm and has been shown to regulate translation and stability of a subset of mRNA transcripts. Three neurological disease-linked de novo TOP3B point mutations outside of the active site have been identified but their impact on TOP3B activity in cells remains poorly understood. Upon establishing a new Neuro2A cell-based TOP3B activity assay, we provide genetic and biochemical evidence that the autism-linked C666R mutation causes accumulation of unresolved TOP3B center dot mRNA covalent intermediates by directly disrupting metal coordination via an atypical D1C3-type metal binding motif within the zinc finger domain. Furthermore, we show that primary neurons are sensitive to TOP3B center dot mRNA covalent intermediates, including those formed by the C666R mutant TOP3B, and that such adducts are capable of causing ribosome collisions. Together, these data identify a previously underappreciated role of the zinc finger domain and how non-active site disease-linked mutations affect TOP3B activity and neuronal toxicity.

Likelihood-free inference for simulator-based statistical models has developed rapidly from its infancy to a useful tool for practitioners. However, models with more than a handful of parameters still generally remain a challenge for the Approximate Bayesian Computation (ABC) based inference. To advance the possibilities for performing likelihood-free inference in higher dimensional parameter spaces, we introduce an extension of the popular Bayesian optimisation based approach to approximate discrepancy functions in a probabilistic manner which lends itself to an efficient exploration of the parameter space. Our approach achieves computational scalability for higher dimensional parameter spaces by using separate acquisition functions, discrepancies, and associated summary statistics for distinct subsets of the parameters. The efficient additive acquisition structure is combined with exponentiated loss-likelihood to provide a misspecification-robust characterisation of posterior distributions for subsets of model parameters. The method successfully performs computationally efficient inference in a moderately sized parameter space and compares favourably to existing modularised ABC methods. We further illustrate the potential of this approach by fitting a bacterial transmission dynamics model to a real data set, which provides biologically coherent results on strain competition in a 30-dimensional parameter space.

BackgroundHybrid effectiveness-implementation designs evaluate the effectiveness and implementation of interventions. We retrospectively evaluated the implementation of a stepped-wedge cluster randomized controlled trial of a facilitated telemedicine model (experimental) integrated into opioid treatment programs (OTPs) compared to offsite referral (control) for hepatitis C virus (HCV) treatment. The trial period was March 2017-October 2022. We compared organizational and implementation characteristics associated with an HCV cure and with high satisfaction with healthcare delivery.MethodsWe used the Reach, Effectiveness, Adoption, Implementation, Maintenance (RE-AIM) framework to guide data collection and evaluation. We evaluated the clinical effectiveness outcome (HCV cure) and patient-centered outcomes (changes between in-person and telemedicine patient satisfaction questionnaire subscales: Time Spent With Doctor and General Satisfaction). We evaluated 7 organizational and 16 implementation variables. We used random forests to obtain a list of variables with total importance weight of at least 95%. We subsequently conducted a configurational comparative method of coincidence analysis (CNA) to identify the variable combinations that are associated with the best outcomes.ResultsThe effectiveness of reach was enhanced by site identification of HCV RNA positive individuals. We found that low patient load per provider or counselor, site liaison presence, and high case manager availability increased clinical effectiveness (i.e., HCV cure). Adoption and implementation, assessed by high healthcare delivery satisfaction among participants in both arms, was associated with site liaisons, frequent case manager onsite presence and consistency, and low provider patient volume. Among telemedicine participants, onsite notifications and provider involvement in recruitment were additional variables associated with high healthcare satisfaction. In referral, providing patient education, low counselor patient volume, case manager involvement in site activities, and high case manager education levels were additional variables associated with high healthcare delivery satisfaction. Intervention maintenance has occurred at 10 sites.ConclusionsCompared to referral, facilitated telemedicine requires fewer variables for high effectiveness and patient satisfaction. The frequent onsite presence and consistency of the case manager and low provider and counselor volumes improved outcomes among both approaches. Improved outcomes among referral participants required more publicity, patient education, higher case manager education, more involvement in site activities, and occurred in university-affiliated sites.Trial registrationClintrials.gov registration number NCT02933970; Comparison of Telemedicine to Usual Care for HCV Management for Methadone-maintained Individuals Full Text View ClinicalTrials.gov.

Zika virus (ZIKV) is an emerging arbovirus, and its infection is often asymptomatic or mild; however, it can lead to severe neurological disorders. Currently, there are no approved treatments or vaccines for ZIKV, highlighting the urgent need to explore potential therapeutic options. In this study, we evaluated the antiviral activity of a novel synthetic peptide (GA-peptide) against ZIKV in vitro. The GA-peptide exhibited dose-dependent inhibition of the virus, affecting multiple stages of the ZIKV replication cycle. It demonstrated virucidal activity and effectively protected Vero cells from ZIKV infection. Additionally, the GA-peptide disrupted viral entry by targeting both the attachment and internalization phases, as well as post-entry stages of the infection. In silico analyses identified potential viral targets that interact with the GA-peptide. These findings underscore the GApeptide's promising potential as a therapeutic agent against ZIKV and its relevance in the development of new antiviral drugs.

Over the past decade, radio frequency (RF) sensing or radar has garnered great interest as an emerging modality to enable human-computer interaction via gesture recognition. Current approaches involve utilization of a radar system that transmits a fixed signal with predetermined frequency, bandwidth, and other waveform parameters. However, gesture recognition accuracy can be greatly impacted by radar transmission parameters, which affect computational load and performance. In this work, we introduce a human-centered, fully adaptive radar (HC-FAR) system for ambient gesture recognition in which a programmable, software-defined radar system dynamically changes its RF transmission in response to human behavior. We design and switch between different transmission modes for different human-computer interaction tasks-human presence detection, trigger detection, and command translation-as well as alter processing so as to minimize computational load. In this way, the proposed HC-FAR paradigm enables dynamic management of the tradeoffs between dimensionality of RF data representations and their resulting computational load with real-time classification accuracy. Our results show that HC-FAR significantly reduces the allocation of computational and spectral resources, while enhancing fine-grain gesture recognition via a joint domain multi-input deep neural network, which takes as input the RF micro-Doppler signature, range, and angle profile.

Mosaic loss of the Y chromosome (mLOY) is the most common somatic event in men, strongly associated with aging and various health conditions. Current methods for detecting mLOY primarily rely on DNA genotyping arrays. Here, we present MosCoverY, a method for estimating mLOY from exome or whole-genome sequencing data. MosCoverY addresses the challenges posed by the structure of the Y chromosome by focusing on single-copy genes and normalizing their coverage against autosomal exons matched by length and GC content. We validated it using data from 212,062 male participants in the UK Biobank, comparing the results to those obtained using genotyping-or whole-genome-sequencing-based methods. MosCoverY identified mLOY in 5.6% of men, demonstrating performance that was comparable to the other methods. We validated our approach by replicating known mLOY associations with age, smoking, all-cause mortality, and germline genetic loci. We further confirmed the robustness of our method at lower sequencing depth and demonstrated its applicability in single-sample analysis. Finally, we used data from The Cancer Genome Atlas to demonstrate that MosCoverY can also reliably detect variable mLOY in tumoral genomes. MosCoverY offers a valuable tool for detecting mLOY from exome or genome data in population-scale studies.

T helper cell subsets-Th1, Th2, and Th17-coordinate pathogen-specific immune responses. Candida albicans-specific T cells include protective Th17 cells alongside other Th subsets. However, the role of alternative Th subsets remains unclear, particularly in individuals with impaired Th17 responses and recurrent candidiasis. Here, we show that patients with STAT1 gain-of-function mutations and chronic mucocutaneous candidiasis have a numerically normal but functionally altered pool of C. albicans-specific Th cells, skewed toward Th1 and Th2. This imbalance persisted even when assessing responses to the known and the newly identified immunodominant C. albicans antigens MP65 (65-kilodalton mannoprotein), HYR1 (hyphally regulated cell wall protein 1), and SAP4-6 (secreted aspartic proteinases 4-6), suggesting that antigen recognition and priming remain intact despite qualitative defects in T cell polarization. Using mucosal infection mouse models, we demonstrate that C. albicans-specific transgenic Th17 cells are sufficient to control infection, whereas Th1 and Th2 cells fail to protect, even in high numbers. Moreover, co-transfer of Th2 cells with Th17 cells impaired fungal control via an IL-4-dependent mechanism. These findings highlight the essential role of Th17 cells in protective immunity against C. albicans and reveal that non-Th17 responses are ineffective and may contribute to susceptibility in both humans and mice.